This invention relates to compounds useful in treating diseases responsive to the activation of melanocortin receptors, particularly the melanocortin-4 receptor (MC4R), to methods of treating such diseases, and to pharmaceutical compositions comprising same.
Melanocortin peptides, particularly α-melanocyte stimulating hormone (α-MSH), are known to have a wide range of effects on biological functions including feeding behavior, pigmentation, exocrine and sexual function (MacNeil et al Eur. J. Pharmacol. 2002, 440, 141–157; Chiesi, M et al. Trends Pharm. Sci. 2001, 22, 247–254; Wikberg, J. E. S et al. Pharm. Res. 2000, 42, 393–420; Wikberg, J. E. S. Eur. J. Pharmacol. 1999, 375, 295–310; and Vergoni, A. V. and Bertolini, A. Eur. J. Pharmacol. 2000, 405, 25–32).
The biological effects of α-MSH are mediated by a sub-family of G protein-coupled receptors, termed melanocortin receptors. There are four melanocortin receptors: MC1R, MC3R, MC4R, and MC5R (MC2R is not a α-MSH receptor but is the adrenocorticotropic hormone (ACTH) receptor; MCXR denotes a generic term for the melanocortin receptors). Activating any one of these receptors results in the stimulation of cAMP formation.
MC1R was first found in melanocytes. Naturally occurring inactive variants of MC1R in animals were shown to lead to alterations in pigmentation and a subsequent lighter coat color. MC3R is expressed in the brain and peripheral tissues, and knockout studies have revealed that MC3R is responsible for alterations in feeding behavior and body weight. MC4R is primarily expressed in the brain. Genetic knock-outs and pharmacologic manipulation of MC4R in animals have shown that agonizing MC4R causes weight loss and antagonizing MC4R produces weight gain. MC5R is ubiquitously expressed in many peripheral tissues and in the brain, but its expression is greatest in exocrine glands. Genetic knock-out of this receptor in mice results in altered regulation of exocrine gland function, leading to changes in water repulsion and thermoregulation.
Evidence for the involvement of melanocortin receptors in obesity includes studies in the agouti mouse. The viable yellow variants of agouti mice (Avy) express the agouti protein both ectopically and within the hair follicle. The agouti protein acts as an antagonist of the MC1R, MC3R, and MC4R receptors. These mice are characterized by maturity-onset obesity, hyperinsulinemia, hyperglycemia in males, yellow coat color, hyperphagia, increased rates of hepatic lipogenesis and decreased rates of lipolysis in indicating that blocking the action of the MC1R, MC3R, and MC4R can lead to the characteristics of the pleiotropic obesity syndrome [Yen, T. T. et al FASEB J. 1994, 8, 479–488].
MC4R knockout mice exhibit the same phenotype as the agouti mice (Avy) and have other characteristics of the pleiotropic obesity syndrome described above [Huszar, D. et al Cell 1997, 88, 131–141]. Rodents injected intracerebroventricularly (ICV) with the cyclic heptapeptide melanotan-II (MT-II), an agonist for the MC1R, MC3R, MC4R, and MC5R receptors, have reduced food intake in several animal feeding models (NPY, ob/ob, agouti, fasted) while ICV injected SHU-9119, a MC3R/MC4R antagonist and MC1R/MC5R agonist, reverses this effect and can induce hyperphagia [PCT WO 99/64002 (Merck)]. Additionally, chronic intraperitoneal treatment of Zucker fatty rats with an α-NDP-MSH derivative (HP228) has been reported to activate MC1R, MC3R, MC4R and MC5R receptors and to attenuate food intake and body weight gain over a 12 week.
Melanocortin receptors may also be viable targets for the control of certain types of sexual dysfunction. Intramuscular administration of melanotan-II (MT-II) within a dose range of 0.005–0.03 mg/kg caused intermittent non-painful penile erections in three normal male volunteers for a period of 1–5 hours after dosing [Dorr, R. T. et al. Life Sciences 1996, 58, 1777–1784. Subcutaneous administration of MT-II (0.025 mg/kg and 0.1 mg/kg) to 10 patients with psychogenic erectile dysfunction caused transient erections (8 responders) with onset from 50–180 min [Wessells, H. et al J. Urology 1998, 160, 389–393].
Several publications have disclosed melanocortin receptor ligands. The compounds of this invention are distinct from and are not suggested by these publications.
Much attention has been focused in the patent literature on melanocortin agonists and their use in treating body weight and sexual disorders [Andersson et al. Exp. Opin. Ther. Patents 2001, 11, 1583–1592]. The first reported non-peptidic melanocortin agonist is shown below. It was isolated from a plant extract from the genus Trichocaulon or Hoodia [WO 98/46243, Quandrant Holdings].

Trega Biosciences has reported a series of aromatic amine structures which have bicyclic terminal groups, typically tetrahydroisoquinolines, and are active at MC3R and MC4R [PCT WO 99/55679]. A typical structure is shown below.

More recently, three patent applications form Melacure Tharapeutics AB disclose a series of indolic amides and guanidines as modulators of MCXR for the treatment of obesity, anorexia, and inflammation [PCT WO 01/55106; PCT WO 01/55107; and PCT WO 01/55109] and are exemplified by the structures shown below.

Melacure also discloses the use of benzylideneaminoguanidines and hydroxyguanidines as melanocortin receptor ligands [PCT WO 02/11715 and PCT WO 02/12178]. Typical structures disclosed in the applications are shown below.

Seven PCT applications from Merck & Co. have disclosed a series of substituted piperidine MC4R agonists useful in the treatment of obesity and sexual dysfunction [PCT WO 99/64002; PCT WO00/74679; PCT WO01/70337; PCT WO10/70708; PCT WO 01/91752; PCT WO02/15909, and PCT WO 03/007949 A1]. The structures in these applications are exemplified below.

Three additional patent applications have appeared from Merck (PCT WO 02/067869; 02/068387; and 02/063388) and are exemplified by structures shown below.

Pfizer has also recently disclosed a number of MC4R agonists [PCT WO/02/00654].

A recent Chiron application has appeared which discloses a series of heterocyclic guanidine derivatives (PCT WO 02/082443).

Two PCT publications from Bristol Myers Squibb have been published and the generic structures are shown below (WO 02/079146 A2 and WO 02/070511 A1).
